A study was initiated of the uptake of tricyclic antidepressant drugs by intact trophozoites of Giardia lamblia. Imipramine, a weak drug, was accumulated by the parasite only 20% less than the more potent drug chlorimipramine. This does not account for the 5-fold difference in lethality of the two drugs. Studies are under way to ascertain if the chlorinated derivative, being more lipophilic, traverses the trophozoite membrane and concentrates in subcellular organelles such as lysosomes, to a greater extent than the unsubstituted compound. Mammalian studies of the effects of the halogenated analogs of imipramine (IMP) showed that the 3-bromo derivative was the most effective uncoupler of oxidative phosphorylation in rat liver mitochondria. The order of effectiveness was Br>C1>F>l>IMP. The halogenated analogs exhibited competitive inhibition of chlorimipramine uptake by G. lamblia trophozoites.